Inherited Abnormalities of

Coagulation
Hemophilia, von Willebrand Disease, and Beyond

a a,b,
Riten Kumar, MD, MSc , Manuel Carcao, MD, MSc, FRCP(C) *

KEYWORDS
 Hemostasis  Hemophilia  von Willebrand disease  Rare factor deficiency

KEY POINTS
 Hemostasis, the arrest of bleeding at the site of vascular injury has been traditionally
divided into primary and secondary hemostasis.
 Primary hemostasis consists of vasoconstriction, platelet adhesion to the subendothelium
via von Willebrand factor, platelet activation and aggregation with the eventual formation
of a platelet plug.
 Secondary hemostasis involves serine protease zymogens (coagulation factors) and their
cofactors which interact sequentially to form cross-linked fibrin which helps stabilize the
initial platelet plug.
 Abnormalities of primary hemostasis classically present with mucocutaneous bleeding,
whereas deficiency of coagulation factors involved in secondary hemostasis may manifest
with joint and muscle bleeds.
 Hemophilia A (HA) and hemophilia B (HB), X-linked deficiencies of factors VIII (FVIII) and IX
(FIX) respectively, are associated with significant morbidity.
 von Willebrand disease, encompassing both quantitative deficiency and qualitative de-
fects of the von Willebrand factor, is thought to be the most common bleeding disorder
in humans.

INTRODUCTION

Bleeding disorders are broadly classified into primary and secondary hemostatic de-
fects (Fig. 1). Primary hemostatic disorders (disorders of platelets and von Willebrand
factor [VWF]) mainly result in mucocutaneous bleeding symptoms such as epistaxis,

Disclosures: None.
a
Division of Haematology/Oncology, Department of Paediatrics, Hospital for Sick Children,
University of Toronto, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada; b Child
Health Evaluative Sciences, Research Institute, Hospital for Sick Children, University of Toronto,
555 University Avenue, Toronto, Ontario M5G 1X8, Canada
* Corresponding author.
E-mail address: manuel.carcao@sickkids.ca

Pediatr Clin N Am 60 (2013) 1419–1441

http://dx.doi.org/10.1016/j.pcl.2013.09.002 pediatric.theclinics.com
0031-3955/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
1420 Kumar & Carcao

Fig. 1. Classification of congenital bleeding disorders.

menorrhagia, petechiae, easy bruising, and bleeding after dental and surgical inter-
ventions. Secondary hemostatic disorders (congenital or acquired deficiencies of
coagulation factors) typically manifest with delayed, deep bleeding into muscles
and joints. This article provides a generalized overview of the pathophysiology, clinical
manifestations, laboratory abnormalities, and molecular basis of inherited abnormal-
ities of coagulation with a focus on hemophilia, von Willebrand disease (VWD), and
rare inherited coagulation disorders (RICD).

OVERVIEW OF HEMOSTASIS

Hemostasis, the arrest of bleeding from a site of vascular injury, is traditionally divided
into primary and secondary hemostatic responses. Primary hemostasis begins imme-
diately after endothelial damage and consists of 4 sequential and overlapping phases:
(1) vasospasm, (2) platelet adhesion to the underlying collagen mediated by VWF, (3)
platelet activation, and (4) platelet aggregation.1–3 The end result of primary hemosta-
sis is the formation of a platelet plug. Primary hemostasis is short lived; once the post-
injury vasospasm abates and blood flow in the damaged vessel increases, the platelet
plug may be rapidly sheared from the injured surface.4 Secondary hemostasis involves
a series of serine protease zymogens and their cofactors, which interact sequentially
on phospholipid surfaces (platelets or damaged endothelial cells) and result in the for-
mation of covalently cross-linked fibrin, which helps stabilize and reinforce the initial
platelet plug.5,6
This sequential activation of serine protease zymogens is called the coagulation
cascade. Historically, the coagulation cascade was divided into the intrinsic and
extrinsic pathways, with the activated partial thromboplastin time (APTT) and prothrom-
bin time/international normalized ratio (PT/INR) being used in clinical and laboratory set-
tings to measure the integrity of the intrinsic and extrinsic pathways, respectively
(Fig. 2).7 Biologic advances over the past few decades have elaborated that in vivo,
instead of occurring in pathways, the coagulation cascade occurs in distinct phases,
namely, (1) initiation, (2) amplification, and (3) propagation.4,8 The coagulation cascade
is initiated when tissue factor (TF), released from the injured endothelial cells and mono-
cytes binds to factor VII (FVII) to form the TF-activated FVII (FVIIa) complex. The TF-FVIIa
complex, in turn, activates factor X (FX) and FIX. Activated FX (FXa) combines with
 Abnormalities of Coagulation 1421

Fig. 2. Schematic representation of the coagulation cascade in-vitro. APTT, activated partial
thromboplastin time; HMWK, high-molecular-weight kininogen; INR, international normal-
ized ratio; PK, prekallikrein; PT, prothrombin time, RT, reptilase time; TT, thrombin time.
(Adapted from Kamal AH, Tefferi A, Pruthi RK. How to interpret and pursue an abnormal
prothrombin time, activated partial thromboplastin time, and bleeding time in adults.
Mayo Clin Proc 2007;82(7):866; with permission.)

activated factor V (FVa) to form the FXa-FVa complex (the prothrombinase complex).
The prothrombinase complex converts small amounts of prothrombin (FII) to thrombin
(FIIa) (initiation phase). The amount of thrombin generated in the initiation phase is inad-
equate (2% of the total amount required) to generate sufficient amounts of fibrin to rein-
force the initial platelet plug.4 The primary role of this initial thrombin is to activate FV,
FVIII, factor XI (FXI), and platelets through a positive feedback mechanism (Fig. 3)
(amplification phase).
The amplification phase is followed by the propagation phase in which activated FIX
(FIXa) binds with FVIIIa to form the FIXa-FVIIIa complex (the tenase complex). The
tenase complex activates FX, which again associates with FVa (forming more prothrom-
binase complex), now leading to the generation of large amounts of thrombin—the so
called thrombin burst. The thrombin generated catalyzes the conversion of fibrinogen
to fibrin, which is covalently cross-linked in the presence of activated factor XIII (FXIIIa)
to yield a stable clot. The propagation phase occurs on the surface of activated plate-
lets. Contact factors of the intrinsic pathway (high-molecular-weight kininogen, prekal-
likrein, and factor XII) are not involved in the propagation phase, thus congenital
deficiencies of these factors, although significantly prolonging the APTT, are not asso-
ciated with bleeding. This article focuses on the main coagulation factor deficiencies
and will not discuss disorders of platelets, which are discussed in another article
appearing in this issue.

HEMOPHILIA
Introduction
HA and HB are X-linked, recessive, bleeding disorders caused by deficiency of blood
coagulation factors FVIII and FIX, respectively. The incidence of HA is estimated to
be 1 in 5000 males, whereas that of HB is 1 in 30,000 males.9,10 Based on the coagula-
tion factor activity level, hemophilia is classified into severe (<0.01 IU/dL), moderate
(0.01–0.05 IU/dL), and mild (0.06–0.4 IU/dL). Overall, severe hemophilia accounts for
1422 Kumar & Carcao

Fig. 3. Schematic representation of the coagulation cascade in vivo. Vascular injury initiates
the coagulation cascade, via release of tissue factor. For the sake of clarity, calcium ions and
phospholipids, 2 important cofactors for most coagulation reactions, have been omitted
from this image. The red box indicates the contact factors, which plays a minimal role in acti-
vation of the coagulation cascade in vivo. The red dashed lines indicate the feedback ampli-
fication loops that follow the initial generation of small amounts of thrombin (FIIa).

40% or more of all hemophilia cases, although the distribution of the different severities
of hemophilia varies; countries with more comprehensive national patient registries
report a higher prevalence of mild hemophilia.11,12 Patients with severe hemophilia typi-
cally develop spontaneous and recurrent bleeds, most commonly into joints (hemarth-
rosis) and muscles, whereas those with mild-moderate hemophilia tend to experience
bleeding related to trauma or surgery.

Molecular Basis and Genetics

Both FVIII and FIX circulate in blood as inactive precursors that are activated at the
time of vascular injury (see Fig. 3). FVIII is a protein cofactor with no intrinsic enzymatic
activity, whereas FIX is a serine protease zymogen with an absolute requirement of
FVIII as a cofactor.13 On activation, FVIIIa and FIXa form the tenase complex, which
activates FX. Thus, the basic biochemical abnormality in patients with hemophilia is
the inability to activate FX and thereby generate thrombin and fibrin to stabilize the
platelet clot. The inheritance pattern of hemophilia is elaborated in Fig. 4.
The genes for FVIII and FIX are located in the long arm of chromosome X at positions
Xq28 and Xq27, respectively.14,15 The FVIII gene spans 186 kb and consists of 28 exons.
The FVIII precursor protein consists of 2351 amino acids, spaced out in 6 domains: (1)
three A domains (A-1, A-2, and A-3), (2) a connecting B domain, and (3) two C-terminal
domains (C-1 and C-2).16,17 Intracellular proteolytic processing of FVIII involves cleavage
at the Arg1689 site (at the B-A3 junction), which results in the formation of a heterodimer
 Abnormalities of Coagulation 1423

Fig. 4. (A) In a mating between a hemophilia carrier woman and an unaffected man, 50% of
the daughters will be carriers and 50% of sons will have hemophilia. (B) In a mating between
an unaffected woman and a man with hemophilia, no son will be affected (having inherited
the Y chromosome from the father) but all daughters will be carriers (having inherited the X
chromosome from the father). Note: very rarely, females may have true hemophilia secondary
to consanguinity in a hemophilic family, skewed inactivation of the normal X chromosome, or
loss of part or all of the normal X chromosome (Turner syndrome).

consisting of an N-terminal heavy chain (A-1, A-2, and partially proteolyzed B domain)
bound noncovalently to a C-terminal light chain (A-3, C-1, and C-2). This heterodimeric
form of FVIII circulates in blood complexed with von Willebrand factor (VWF). Activation
of FVIII by thrombin involves (1) release of FVIII by VWF and (2) excision of the remnant
B domain.17 The FIX gene is much smaller; it is 34 kb long and consists of 8 exons.13,18
FIX consists of 416 amino acids and requires posttranslational, vitamin K-dependent,
g-glutamylcarboxylation to become physiologically active.
As of November 2012 more than 2000 unique mutations in the FVIII gene have been
recorded in an international database (HAMSTeRS [The Hemophilia A Mutation, Struc-
ture, Test and Resource Site]; http://hadb.org.uk/). The most common mutation in HA,
affecting nearly 45% of patients with severe disease, is an intron 22 inversion.19,20 A
similar database recording mutations for HB is accessible at http://www.umds.ac.
uk/molgen/haemBdatabase. Inversion mutations are not seen in HB, and most pa-
tients (z70%) have missense mutations.18 HB Leyden is a rare variant of HB that oc-
curs secondary to point mutations in the promoter region of the FIX gene. Typically,
patients with this mutation present with severe HB (FIX<0.01 IU/dL) in early childhood.
However, postpuberty, increased androgen production results in increased FIX pro-
moter activity and increased FIX production (eventually reaching z 0.5 IU/dL), thereby
correcting the hemophilia phenotype.21

Clinical Presentation and Diagnosis

About 50% to 70% of newborns with hemophilia have a family history of the dis-
ease.16,22 Diagnosis of HA in this subcohort is usually made early in life by measuring
the FVIII level on the cord blood. FIX levels, however, are physiologically low in the
1424 Kumar & Carcao

neonatal period (see Table 1), and a low FIX level in the cord blood, needs to be
repeated at 6–12 months, before a diagnosis of HB can be confirmed. FIX levels in-
crease throughout early childhood, and therefore, the ultimate classification of a pa-
tient’s HB severity may change with aging, that is, a child labeled with moderate HB
in the first year of life may ultimately be labeled as having mild HB. In the remaining
30% to 50% of patients without a positive family history, the diagnosis is usually
made later in life, once the neonate or toddler is worked up for bleeding symptoms.
Screening laboratory tests in patients with hemophilia usually demonstrate a prolonged
APTT with a normal PT/INR value (see Fig. 2). Diagnosis can be confirmed by demon-
strating a low or absent FVIII or FIX coagulant activity. This is typically measured in
platelet-poor plasma using a functional clotting assay (usually a one-stage APTT-
based assay), although some laboratories may use a two-stage or chromogenic
substrate assay.16 Of note, low FVIII and FIX activity levels do not always indicate he-
mophilia. A differential diagnosis of low plasma factor levels is elaborated in Table 1.
Clinical manifestations of HA and HB are identical, although there is some suggestion
that HB may be milder than HA for the same level of factor activity.23 Bleeding is the

Table 1
Differential diagnosis of low FVIII and FIX levels

Factor Condition Associated with Low Factor Level

FVIII Type 3 VWD  FVIII level usually ranges between 0.02 and 0.05 IU/dL
 Associated reduction in VWF:Ag and VWF:RCo activity
(see section on VWD for details)
FVIII Type 2N VWD  Caused by specific mutations in the VWF gene that
result in reduced binding of FVIII by VWF
 FVIII level usually range between 0.05 and 0.4 IU/dL;
VWF:Ag and VWF:RCo activity are usually normal
 Distinguished using the VWF:FVIII binding assay
and/or genetic analysis
FVIII Combined deficiency  Very rare (1 in a million)
of FV and FVIII  Generally causes FVIII levels in the 0.2 IU/dL range
 Caused by mutations in genes encoding for
intracellular transport protein (LMAN1 and MCFD2)
 APTT and PT/INR are both prolonged
FVIII Acquired hemophilia  Very rare in children (0.045 in a million)
 Associated with infection, penicillin antibiotics, and
autoimmune conditions
 Abnormal incubated mixing study
 Bethesda assay or Nijmegen modification of Bethesda
assay may be used to quantify inhibitor titer
FIX Neonatal age  FIX levels are low in healthy neonates
 Low FIX levels in a newborn should be rechecked at
6–12 mo of age
FIX Acquired vitamin  Liver disease, malabsorption, prolonged antibiotic use,
K deficiency and coumadin
 Associated reduction in other Vitamin-K-dependent
proteins (FII, FVII, FX)
FIX Congenital deficiency of  Mutations in GGCX or VKOR gene
Vitamin-K-dependent  Associated reduction in other Vitamin-K-dependent
clotting factors proteins (FII, FVII,FX)

Abbreviations: GGCX, g-glutamylcarboxylase; LMAN1, lectin mannose-binding 1; MCFD2, multiple

coagulation factor deficiency 2; VKOR, vitamin K epoxide reductase.
 Abnormalities of Coagulation 1425

clinical hallmark of hemophilia, but the sites and pattern of bleeding vary significantly
based on disease severity and age of patients.16,24 Birth is thought to be the first hemo-
static challenge for a newborn with hemophilia. In a large prospective study of 580 in-
fants with hemophilia, enrolled in the Universal Data Collection of the Center for
Disease Control and Prevention, 53% of infants with hemophilia had a bleeding episode
by the age of 1 month.25 Bleeding post circumcision accounted for almost half (47.9%)
of the bleeds in the first month of life; this was followed by head bleeds (19.4%) and
bleeding from heel sticks (10.4%).25 Intracranial hemorrhage (ICH) remains the most
serious complication of hemophilia in the immediate postnatal period and can result
in severe morbidity or death. Recent studies have indicated that the rate of ICH in new-
borns with hemophilia (all severities) ranges from 1% to 4%, which is significantly higher
than in newborns who do not have a bleeding disorder.25–27 The optimal mode of deliv-
ery for a woman known to be a hemophilia carrier has been extensively debated.28,29
However, it is clear that caesarean delivery does not completely eliminate the risk of
ICH, and consequently, in most centers, the recommended mode of delivery remains
an atraumatic, non–instrument-assisted vaginal delivery. In a prospective European
study, assisted vaginal delivery with instrumentation was associated with a marked
increased risk of head bleeds (odds ratio [OR], 8.84; 95% confidence interval [CI],
3.05–25.5), and it is generally accepted that instrumentation of any kind (forceps, vac-
uum extraction, or fetal scalp electrodes) should be avoided in infants born to known
carriers of hemophilia.26 For newborns with a clinical suspicion of an ICH, factor should
be administered immediately and prior to imaging confirmation.30 When the hemophilia
subtype (HA vs HB) is not known, it may be appropriate to administer fresh frozen
plasma (FFP) (10–15 mL/kg) while awaiting laboratory confirmation.16 It is also recom-
mended that intramuscular vitamin K should be avoided until the diagnosis of hemophil-
ia is excluded, and oral vitamin K may be administered in the interim or once the
diagnosis of hemophilia is confirmed.30
Bleeding from the oral mucous membranes becomes more common as infants with
hemophilia grow older.25 Other sites of bleeding that become apparent by 6 to
12 months of age include bleeding into joints (hemarthrosis), muscle bleeds, and
bleeding from the gastrointestinal and urinary tracts. ICH remains a serious complication
of hemophilia at all ages. In a nested case-control study of more than 10,000 patients
with hemophilia, older than 2 years, 2% of patients had experienced an ICH with a
20% mortality rate.31 High titer inhibitors (OR, 4.01; 95% CI, 2.40–6.71), prior ICH
(OR, 2.62; 95% CI, 2.66–4.92), and severe hemophilia (OR, 3.25; 95% CI, 2.01–5.25)
were found to be independent predictors of ICH.
Hemarthrosis is the clinical hallmark of severe hemophilia. Although all synovial
joints are at potential risk, the most frequently affected are the knees, elbows, and
ankles. Joint bleeds usually become apparent once the toddler starts bearing weight.
The range of ages at which children experience a first joint bleed varies tremendously.
In a Dutch study, the median age of first joint bleed was 1.8 years but the range was
between 0.2 and 5.8 years.32 This marked variation in the age at which children with
severe hemophilia experience their first joint bleed reflects the considerable heteroge-
neity that exists in the bleeding phenotype of patients with severe hemophilia. Differ-
ences in levels of physical activity, structural integrity of joints, and coinheritance of
pro-thrombotic conditions, particularly Factor V Leiden mutation, have been proposed
as possible explanations for this heterogeneity.16,33,34
Bleeding into a joint results in synovial hypertrophy and inflammation (synovitis). A
joint that undergoes repeated bleeds is referred to as a target joint. While the exact
definition of a target joint is debatable, it usually refers to a joint that develops 3 or
more bleeds in a period of 3 to 6 months.16 A target joint may eventually develop
1426 Kumar & Carcao

hemophilic arthropathy, characterized by loss of joint space, cystic changes within the
subchondral bone, osteoporosis, and atrophy of the surrounding muscles.16,35 The
final stage of hemophilic arthropathy is a deformed and dysfunctional joint, which
may significantly compromise a patient’s quality of life (Fig. 5).
Muscle hematomas, the second most common type of bleeding in patients with he-
mophilia account for 10% to 25% of all bleeds in this cohort.36 Bleeding into the iliop-
soas muscle, a large muscle in the pelvis, is particularly concerning because patients
can lose a significant volume of blood into this muscle. Inadequate or delayed treatment
of muscle hematomas may result in compartment syndrome, atrophy of tendons,
myositis ossificans, and rarely hemophilic pseudotumors. Pseudotumors result from
recurrent hemorrhage into an enlarging, encapsulated hematoma and may lead to pres-
sure necrosis and destruction of adjacent structures.37

Clinical Management
General overview
Management of hemophilia is complex and requires a multi-disciplinary comprehen-
sive care approach involving hematologists specialized in bleeding disorders, dedi-
cated nurses, social workers, physiotherapists as well as the availability of dentistry,
orthopedics, and psychology. It is recommended that all patients with hemophilia be
followed in comprehensive hemophilia treatment centers able to provide such multi-
disciplinary care. Education of patients and primary care providers about risks of
bleeding and related complications is important. Lifestyle modifications including
avoidance of contact and collision sports, routine dental care to reduce the risk of
gingival bleeding, avoidance of platelet-impairing medications (aspirin and nonste-
roidal antiinflammatory drugs), and use of MedicAlert bracelets should be encouraged.
Given the risk of exposure to blood-derived products, patients should be vaccinated
against hepatitis B. Vaccinations for patients with hemophilia can, and ideally should,
be given subcutaneously, using the smallest gauge needle, with local pressure applied
for at least 5 minutes.

Fig. 5. A 12-year-old boy with severe hemophilia B had received minimal treatment for he-
mophilia before immigrating to Canada. At presentation to our clinic, he showed significant
arthropathy of his right knee. (A) Photograph of the legs showing valgus deformity, limb
length discrepancy, and loss of normal landmarks of the right knee with diffuse muscle
wasting. (B) Radiograph of the legs shows valgus deformity, loss of joint space, osteopenia,
and deformity of the medial femoral condyle and tibial plateau. (C) Preoperative computed
tomography shows sclerosis and irregularity of the distal femoral physis and anterolateral
physeal fusion at the distal femur growth plate (architecture of the left knee is relatively
preserved). ([A] Courtesy of Ms Pamela Hilliard, BSc (PT), Department of Rehabilitation
Services, Hospital for Sick Children.)
 Abnormalities of Coagulation 1427

Management of acute bleeds

Factor replacement Treatment needs to be administered expeditiously in the case of
acute bleeds to prevent both short-term complications and long-term disabil-
ities.38,39 Factor replacement therapy using FVIII and FIX concentrates forms the
backbone of management for patients with severe hemophilia. These concentrates
may be broadly divided into 2 categories: plasma-derived and recombinant concen-
trates. The dose of concentrate to be administered is calculated based on the hemo-
philia subtype, baseline factor activity, and desired increase in the factor level.
Generally, 1 U/kg of administered FVIII increases the plasma FVIII coagulant activity
by 0.02 IU/dL; whereas 1 U/kg of recombinant FIX increases the plasma FIX coag-
ulant activity by approximately 0.008 IU/dL (the expected increase is 0.01 IU/dL
when using plasma-derived FIX).16 The half-life of FVIII is 8 to 12 hours and that of
FIX is 12 to 24 hours.40,41 Factor concentrates may be administered in bolus doses
or through continuous infusion. Continuous infusion of factor prevents the peaks and
troughs associated with bolus dosing and may be particularly useful in surgical and
postsurgical settings.24 A bolus dose of 50 U/kg of FVIII or FIX followed by an initial
continuous infusion of 2 to 3 U/kg/h of FVIII or 4 to 8 U/kg/h of FIX is recommended
with periodic measurement of factor levels to ensure that they are being maintained
in the hemostatic range.24,42,43 For mild-moderate hemorrhage, the targeted hemo-
static range is 0.3 to 0.4 IU/dL for FVIII and 0.25 to 0.3 IU/dL for FIX, whereas for
severe life-threatening hemorrhages, the target range is 1 IU/dL.44 For details on
the specific dose of factor used and duration of therapy, see article by Robertson
and colleagues.45
Local measures Mild superficial bleeding symptoms in patients with mild-moderate he-
mophilia may be managed with local measures. Compression, use of gelatin sponge or
gauge soaked in tranexamic acid may be tried for superficial wounds. Epistaxis may be
managed by nasal packing and use of topical thrombin (eg, Thrombi-Gel, Evithrom) and
fibrin sealant gel (Evicel).
Desmopressin Desmopressin (1-deamino-8-D-arginine-vasopressin; DDAVP), a syn-
thetic analog of the antidiuretic hormone, vasopressin, exerts its procoagulant effect
by causing the release of stored VWF and FVIII from Weibel-Palade bodies in endothe-
lial cells into the plasma thus increasing (doubling or tripling) the circulating levels of
FVIII and VWF.46 Clinically meaningful response is usually seen only in patients with
a baseline FVIII activity of more than 0.10 to 0.15 IU/dL.47 DDAVP does not increase
FIX levels and therefore is not useful in patients with HB. It is important to know a priori
how a patient will respond to DDAVP before using it in a clinical setting. This informa-
tion is usually obtained by administering the standard dose of 0.3 mg/kg (maximum
20 mg) of DDAVP intravenously/subcutaneously or intranasally (150 mg [for children
weighing <50 kg] or 300 mg [for children weighing 50 kg]) and monitoring the FVIII
and VWF response at 1 and 4 hours (DDAVP challenge test). Younger patients (eg,
<3–5 years of age) often have a suboptimal response to DDAVP, and the DDAVP chal-
lenge should be repeated in patients who were assessed as nonresponders at a young
age. For patients who respond, DDAVP may be used to treat minor bleeds and for pro-
phylaxis before dental and minor surgical procedures. Peak FVIII levels are reached
within 30 to 60 minutes after intravenous injection and 90 to 120 minutes after intra-
nasal and subcutaneous administration. Side effects of DDAVP include fluid retention
and hyponatremia, and patients should be advised to limit their fluid intake for 24 hours
after DDAVP administration. For the same reason, DDAVP is avoided in children
younger than 2 years. The ability of DDAVP to increase FVIII and VWF levels is lost
after multiple doses.
1428 Kumar & Carcao

Antifibrinolytic agents Lysine analogs, tranexamic acid (cyclokapron) and ε-amino-

caproic acid (Amicar), are usually used in combination with other therapeutic modalities
(FVIII or FIX concentrates or DDAVP). They are particularly useful in patients with
epistaxis, gingival bleeding, and menorrhagia and may also be used for prevention of
bleeding after minor surgical and dental procedures. Both agents can be used orally
and intravenously. The dose of tranexamic acid is 15 to 25 mg/kg orally, taken 3 to 4
times a day (or 10 mg/kg intravenously every 8 hours). This drug is also available as a
mouthwash (10 mL of a 5% solution taken 4 to 6 times a day), which if swallowed is
equivalent to a dose of 500 mg. Common side effects are nausea and diarrhea, which
are dose dependent. Antifibrinolytics are contraindicated in hematuria given the risk of
clot formation within the renal collecting system.

Long-term management: prophylaxis versus episodic therapy

In the 1950s, Nilsson and colleagues48 in Malmö, Sweden, observed that patients with
moderate hemophilia rarely develop chronic arthropathy and disability.49 They hypoth-
esized that by prophylactically replacing FVIII/FIX concentrates on a regular basis, they
could convert the phenotype of patients with severe hemophilia to a moderate one and
thereby prevent recurrent hemarthrosis and arthropathy. Almost 25 years later, Profes-
sor Nilsson published data on 60 patients who had received prophylactic factor replace-
ment for 2 to 25 years; and demonstrated that when prophylaxis was started early and
administered regularly, patients with severe hemophilia had significantly reduced
bleeding, excellent joint status, and were able to lead normal lives.50 The superiority
of prophylaxis (regular administration of factor to patients with hemophilia to prevent
bleeding episodes) over on-demand therapy (administration of factor only at the time
of an acute bleed) was demonstrated in a landmark randomized trial published by
Manco-Johnson and colleagues51 in 2007.
Prophylaxis is now the standard of care for patients with severe hemophilia in the
developed world. Full-dose primary prophylaxis entails the administration of high
doses of factor (25–40 U/kg), every other day for HA and twice a week for HB starting
by 2 years of age and before the onset of joint damage.38 The biggest disadvantage of
this regimen is the need for frequent infusions of factor starting at a very young age,
which leads to a high need for central venous access devices (CVADs). Although
CVADs allow the early initiation of prophylaxis and home therapy, they are associated
with a substantial rate of infections and thrombosis.52 An alternative approach to start-
ing very young children on full-dose prophylaxis is to instead use escalating dose/fre-
quency prophylaxis. Such an approach starts patients on once-a-week infusions, then
escalates them to twice-a-week prophylaxis, and finally moves them to full-dose pro-
phylaxis. Some countries, notably Sweden, escalate all children quickly to full-dose
prophylaxis regardless of whether these children are experiencing bleeds, whereas
other groups, instead, only escalate patients if they experience what is judged to be
an unacceptably high bleeding frequency (tailored prophylaxis).53 A head-to-head
comparison between tailored prophylaxis and full-dose prophylaxis has not been
done.

The Future of Hemophilia Care

Long-acting factor concentrates
The management of hemophilia is likely to change with the development of longer
acting FVIII and FIX concentrates.54 Several companies, using different technologies
(PEGylation, fusion to albumin or the Fc component of immunoglobulin), have already
shown a 3- to 6-fold prolongation in the half-life of FIX. These products are still under-
going clinical trials, although preliminary data seem promising. Similar technologies are
 Abnormalities of Coagulation 1429

being used to develop long-acting FVIII concentrates, but so far, these technologies
have only been able to result in a 1.5 to 1.7 prolongation of the half-life of FVIII.
Gene therapy
In 2011, the first successful results of gene therapy for HB were published.55 Six pa-
tients with severe HB (FIX<0.01 IU/dL) were treated with 3 escalating dose levels of an
adenovirus-associated virus vector expressing a codon-optimized human FIX gene. A
transient elevation of liver enzymes observed in 2 patients treated with the highest
vector dose was rapidly cleared with a short course of steroids. Other than this there
was no acute toxicity observed over 6 to 16 months of follow-up. FIX coagulant activity
trough levels of 0.02 to 0.11 IU/dL were observed in all patients, and 4 of 6 patients
were able to discontinue prophylaxis. Further studies evaluating the safety and
long-term efficacy of gene therapy are underway.
Inhibitors in Hemophilia
Development of inhibitors is currently the most serious complication of hemophilia.
Inhibitors are neutralizing allo-antibodies that develop in 30% or more of patients
with HA and about 2%to 5% of patients with HB.56 These antibodies, which usually
develop within the first 20 to 50 exposure days to factor, rapidly inactivate infused fac-
tor, rendering replacement therapy ineffective and are associated with significant
morbidity. Risk factors for inhibitor development16 include genetic factors such as fam-
ily history of inhibitor, race, underlying mutation and polymorphisms in immune regula-
tory genes (interleukin-10, tumor necrosis factor-a, and cytotoxic T-lymphocyte
antigen-4),57,58 as well as acquired risk factors, for example, intense exposure to fac-
tor, particularly during surgery, hemorrhage, and vaccination. It is thought that these
conditions act as danger signals to the immune system, resulting in upregulated immu-
nity, and increase the risk of antibody development. The immunogenicity of recombi-
nant versus plasma-derived factor concentrates has been a subject of intense
debate.38,59–61 A randomized prospective study (Survey of inhibitors in plasma-prod-
uct exposed toddlers [SIPPETT trial]) is currently ongoing to address this issue.
Inhibitors levels are measured using the Bethesda assay and are quantified in
Bethesda units (BU; 1 BU is the amount of antibody that inactivates 50% of factor after
2 hours of incubation at 37 C). A low-titer inhibitor is defined as less than 5 BU, and a
high-titer inhibitor is defined as 5 BU or more. Management of inhibitors is complex
and essentially includes 2 aspects:
1. Management and prevention of acute bleeds: acute bleeds in patients with low-titer
inhibitors may be managed by giving high doses of FVIII or FIX. In patients with
high-titer inhibitors, bypass agents (activated prothrombin complex concentrates
[FEIBA] and/or recombinant FVIIa [NovoSeven]) may be used. In a prospective,
randomized, open-label, crossover trial, both products were equally efficacious.62
These bypass agents can also be used in a prophylactic manner to prevent
bleeding.
2. Immune tolerance therapy: Permanent eradication of inhibitors can be achieved
using immune tolerance induction (ITI). ITI entails the frequent administration of large
doses of factor concentrate, and when successful, results in normalization of factor
pharmacokinetics and subsequent improvement in the patient’s quality of life. ITI has
been mainly studied in HA inhibitor patients where success rates of 60% to 80%
have been reported.56 Different regimens of ITI have been reported. A recent ran-
domized trial comparing low-dose (50 U/kg 3 times/wk) and high-dose (200 U/kg/
day) ITI showed similar efficacy, although high dose was associated with quicker
success and less bleeding while on ITI.16,63 Readers interested in learning details
1430 Kumar & Carcao

about the diagnosis and management of inhibitors are referred to the following excel-
lent reviews.64,65

VON WILLEBRAND DISEASE

Introduction
VWD is the most common inherited bleeding disorder in humans. Large, epidemiologic
studies, measuring von Willebrand activity in healthy school children estimated the
prevalence to be 1 in 100,66,67 although the prevalence of clinically symptomatic
VWD is probably closer to 1 in 1000.68 VWD occurs secondary to a mild or severe quan-
titative deficiency (type 1 or type 3, respectively) or a qualitative defect (type 2) in VWF,
a large, adhesive, multimeric glycoprotein. VWD is generally milder than hemophilia
with most patients manifesting mucocutaneous bleeding symptoms and postoperative
hemorrhage. VWF plays an important role in both the primary and secondary hemostat-
ic pathways:
1. Platelet adhesion to the underlying subendothelium is mediated by VWF, which
binds to platelet surface glycoprotein GPIb/IX/V.
2. Platelet aggregation is mediated by both VWF and fibrinogen, which bind to the
platelet surface glycoprotein GPIIb/IIIa.
3. VWF binds and stabilizes FVIII in circulation, protecting it from degradation by
activated protein C.

Molecular Basis and Genetics

The VWF gene, cloned in 1985, is located at the tip of the short arm of chromosome 12
at 12p13.3.69,70 The gene spans 178 kb, consists of 52 exons, and codes for a protein
consisting of 2813 amino acids.71 VWF is synthesized in vascular endothelial cells and
megakaryocytes and undergoes significant posttranslational modification including
dimerization, sulfation, and glycosylation.72 The final protein is either constitutively
released from endothelial cells into plasma or stored in Weibel-Palade bodies of endo-
thelial cells and then secreted into plasma in the setting of stress or bleeding. VWF
produced in megakaryocytes is stored within platelet alpha granules. On activation
of platelets, this VWF participates in hemostasis but is not secreted into plasma.
When in circulation, the molecular weight of VWF ranges from 500 (short VWF multi-
mers) to 20,000 (high-molecular-weight multimers) kDa depending on the extent of
multimerization. Multimer size is an important determinant of the functional activity
of VWF, as high-molecular-weight-VWF (HMW-VWF) is most physiologically active.
The molecular weight of VWF is controlled by the metalloprotease enzyme,
ADAMTS13 (a disintegrin and metalloprotease with thrombospondin 1 motif, member
13), which cleaves VWF between Tyr1605 and Met1606 residues in the A2 domain.73
The molecular basis of VWD has only recently begun to be characterized. Identifying
a genetic basis for type 1 VWD, the most common variant, has proven to be particu-
larly challenging with 3 large cohort studies identifying a putative mutation in only 65%
of the tested subjects.74–76 Inherited in an autosomal dominant manner, type 1 VWD
has incomplete penetrance and expression, and as such, genetic testing, outside of a
research study, is not recommended for diagnosing type 1 VWD. Type 2 VWD is
inherited largely in an autosomal dominant manner (with the exception of type 2N,
which is autosomal recessive) and usually occurs secondary to missense mutations.69
The rare, type 3 VWD is autosomal recessive, with both parents carrying mutations in
the VWF gene. Details of mutations identified in the VWF gene may be found through
the International Society on Thrombosis and Haemostasis (ISTH)-sponsored data-
base: http://www.vwf.group.shef.ac.uk/.
 Abnormalities of Coagulation 1431

Classification and Laboratory Diagnosis

The current classification of VWD was established in 2006.77 VWD is classified into 3
main categories: type 1 includes partial quantitative deficiency, type 2 includes qual-
itative defects, and type 3 VWD is associated with a complete deficiency of VWF
(Table 2). Type 2 VWD is further subclassified into 4 secondary categories (A, B, M,
and N), Laboratory evaluation of VWD includes the use of nonspecific tests such as
the complete blood cell count (CBC), APTT, and FVIII activity, as well as tests specific
for VWF. The platelet function analyzer (PFA-100) provides an in vitro measure of
primary hemostasis under conditions of high shear using disposable cartridges con-
taining collagen/epinephrine or collagen/adenosine diphosphate.78 In a prospective
study of 53 children with VWD, the sensitivity of PFA-100 for detecting VWD was
90%,79 potentially allowing PFA-100 to be used as a screening test for VWD. Tests
specific for VWF include measurement of the amount of circulating von Willebrand an-
tigen (VWF:Ag) and measurement of von Willebrand function through either a
ristocetin-based platelet aggregation study, known as von Willebrand ristocetin
cofactor assay (VWF:RCo), or through a von Willebrand collagen binding assay.70
The VWF:RCo to VWF:Ag ratio helps differentiate type 1 from type 2 A, B, and M
VWD. In type 1 VWD, there is a proportionate decrease in the antigen and activity,
and therefore the VWF:RCo/VWF:Ag is greater than or equal to 0.6. Conversely, in
type 2 (A, B, and M) VWD, there is a disproportionate decrease in the VWF activity
such that the VWF:RCo/VWF:Ag is less than 0.6. Other tests that aid in identification
of the type 2 VWD subtypes include the ristocetin-induced platelet aggregation (RIPA;
distinguishes type 2B from the others) and VWF multimer analysis (mainly used to
differentiate type 2A from type 2M).

Type 1 VWD
Type 1 VWD accounts for 75% to 80% of all cases of VWD. Clinical diagnosis of type 1
VWD remains challenging because there are multiple factors such as patient age and
blood group that contribute significantly to plasma VWF levels.69 Plasma VWF levels
increase by 1% to 2% per year of age and are 25% higher in individuals with non–
blood group O than in those with blood group O.80,81 VWF is also an acute-phase
reactant, and plasma levels may be high in conditions of stress, inflammation, exer-
cise, and pregnancy and in women using oral contraceptives. To make matters
even more complicated, the plasma level of VWF, used as a cutoff to make the

Table 2
Laboratory findings in von Willebrand disease

VWF:RCo/
Disease VWF:Ag Multimer
Subtype VWF:Ag VWF:RCo Ratio FVIII Level Pattern RIPA
1 Y Y >0.60 Y or 4 Normal 4
2A Y YY <0.60 Y or 4 Abnormal Y
2B Y YY <0.60 Y or 4 Abnormal [
2M Y YY <0.60 Y or 4 Normal Y
2N Y or 4 Y or 4 >0.60 0.10–0.40 IU/dL Normal 4
3 <0.05 IU/dL <0.05 IU/dL NA <0.10 IU/dL Absent Absent

[, elevated/raised; Y, mild reduction; YY, severe reduction; 4, normal.

Abbreviations: NA, not applicable; RIPA, ristocetin-induced platelet aggregation; VWF:Ag, von
Willebrand antigen; VWF:RCo, von Willebrand ristocetin cofactor assay.
1432 Kumar & Carcao

diagnosis of type 1 VWD, remains a matter of debate.82 Different cutoffs ranging from
0.15 to 0.50 IU/dL have been suggested in the literature but with no consensus.70,77,79
Using a cutoff of 0.40 IU/dL for both VWF:Ag and VWF:RCo seems to be practical and
avoids both overdiagnosing and underdiagnosing VWD. CBC and PT/INR usually have
normal values in type 1 VWD. The FVIII activity and consequently the APTT may have
abnormal values when the VWF:Ag is <0.35 IU/dL, although a normal value of APTT by
no means rules out VWD.70

Type 2 VWD
Type 2 VWD accounts for 20% to 25% of all VWD cases and is characterized by a
VWF:RCo/VWF:Ag less than 0.6. Clinical presentation of type 2 VWD is similar to
that of type 1 VWD.
Type 2A VWD Type 2A VWD is characterized by the selective loss of high- and
medium-molecular-weight multimers either secondary to a defect in the synthesis of
these multimers or due to increased cleavage of the multimers by ADAMTS13.70
VWF multimer analysis can aid in the diagnosis (Fig. 6).

Type 2B VWD Type 2B VWD is caused by gain-of-function mutations in the GPIb/IX/V

binding site of the von Willebrand gene, causing spontaneous binding of VWF to plate-
lets and the subsequent removal of the HMW-VWF multimers together with platelets
from the circulation.6 Patients may have thrombocytopenia, which can be aggravated
by conditions associated with increased VWF secretion. Type 2B VWD is also associ-
ated with loss of high-molecular-weight multimers (see Fig. 6). This condition may be
differentiated from type 2A VWD by performing an RIPA assay. Type 2B VWD typically
shows hyperresponsiveness with low-dose ristocetin, whereas the RIPA is reduced in
type 2A.
Type 2M VWD Type 2M VWD occurs secondary to decreased interaction between
VWF and platelets. VWF multimer analysis distinguishes type 2A from type 2M; in
the former, multimer distribution is abnormal, whereas in the latter, it is typically
normal.

Fig. 6. VWF multimer analysis in 2 patients who have type 2 VWD. Lanes 1 and 4 represent
normal plasma multimer patterns. Lane 2 shows the plasma VWF multimers for a patient
who has type 2A, and lane 3 shows the plasma multimers for a patient who has type 2B
VWD. HMW, high molecular weight; LMW, low molecular weight. (From Robertson J,
Lillicrap D, James PD. Von Willebrand disease. Pediatr Clin North Am 2008;55(2):382. viii–ix;
with permission.)
 Abnormalities of Coagulation 1433

Type 2N (Normandy) VWD Type 2N VWD, an autosomal recessive variant of VWD,

occurs secondary to mutations in the FVIII binding site in the von Willebrand gene
and may be misdiagnosed as mild or moderate hemophilia.83 The values of VWF:Ag
and VWF:RCo may be borderline low or normal, with a disproportionate decrease in
the FVIII activity (FVIII activity: 0.05–0.4 IU/dL). RIPA and VWF multimer pattern are
normal. The diagnosis is made either using an enzyme-linked immunosorbent
assay-based VWF:FVIII binding assay or by genetic analysis of the VWF gene.
Type 3 VWD
Type 3 VWD is a rare autosomal recessive variant of VWD. Patients present with se-
vere mucocutaneous and hemophilia-like bleeding (hemarthrosis and muscle bleeds)
early in life. The VWF:Ag and VWF:RCo are less than 0.05 IU/dL, with an FVIII activity
less than 0.1 IU/dL.
Clinical Management
Anticipatory guidance, education of patients and parents, and use of local measures
and antifibrinolytics is similar to hemophilia (please see preceding section on “clinical
management of hemophilia”). Additional therapeutic interventions specific for VWD
are elaborated.
Estrogens
Estrogen-containing oral contraceptive pills may be used for females with menor-
rhagia. Estrogen ointment (Premarin) has been used intranasally on a prophylactic
basis for pediatric patients with recurrent epistaxis with some success.84
Desmopressin
Over 80% of patients with type 1 VWD will show a response to DDAVP,85 although
response in type 2 VWD is less predictable. DDVAP is not beneficial in type 3 VWD,
and given the risk of exacerbating the thrombocytopenia, it is usually contraindicated
in type 2B VWD. Similar to hemophilia, it is important to perform a DDAVP challenge
test before using it in a clinical setting. Dose and side effects of DDAVP are elaborated
in the hemophilia section of this article.
VWF/FVIII concentrate
For life-threatening bleeds, major surgery, and for patients in whom DDAVP is either
contraindicated (type 2B VWD) or not beneficial (all patients with type 3 and those
with type 2 or 1 VWD shown to be inadequate responders to DDAVP), viral-
inactivated, plasma-derived, VWF/FVIII concentrates are the treatment of choice. There
are several products available that are differentiated based on the ratio of VWF to FVIII.
Infusions are usually given every 12 to 24 hours. For patients requiring repeated infu-
sions of VWF/FVIII concentrates, it is recommended that trough FVIII and VWF levels
be measured to ensure that the patient does not have supra-physiological levels of FVIII,
which may be associated with an increased risk of thrombosis.70 A recent retrospective
study showed that prophylaxis with VWF/FVIII concentrates is safe and efficacious in
patients with severe VWD.86 For details about VWD management, readers are referred
to the following excellent reviews.82,87

RARE INHERITED COAGULATION DISORDERS

RICD account for 3% to 5% of all coagulation disorders and include qualitative and
quantitative deficiencies of fibrinogen (afibrinogenemia, hypofibrinogenemia, and dysfi-
brinogenemia), prothrombin (FII), FV, combined FV and FVIII, FVII, FX, FXI, and FXIII.88–90
These conditions are inherited in an autosomal recessive manner with affected
 1434
Kumar & Carcao
Table 3
Prevalence, molecular basis, and clinical characteristics of rare inherited coagulation disorders

Coagulation Half-life of
Deficient Factor Prevalence Gene Involved Clinical Features Assays Factor Replacement Factor
Afibrinogenemia 1 in 1 million FGA (4q31.3) Umbilical stump bleeding, CNS bleeds, hemarthrosis PT[ pd Fibrinogen, 2–4 d
FGB (4q31.3) and recurrent first-trimester pregnancy loss; APTT[ cryoprecipitate,
FGG (4q32.1) splenic rupture and rarely thrombosis TT[ FFP
Prothrombin (FII) 1 in 2 million F2 (11p11.2) Complete deficiency not compatible with life; PT[ FFP, PCCs 3–4 d
mucosal bleeds, hemarthrosis, and muscle APTT[
hematomas TT4
FV 1 in 1 million F5 (1q24.2) Mucosal bleeds, hemarthrosis, and muscle PT[ FFP 36 h
hematomas APTT[
TT4
Combined 1 in 1 million LMAN1 (18q21.32) Mucosal bleeds PT[ FFP 1 pdFVIII/rFVIII As for individual
FV 1 FVIII MCFD2 (2p21) APTT[ factors
TT4
FVII 1 in 500,000 F7 (13q34) Mucosal bleeds, hemarthrosis, and muscle PT[ pdFVII, rFVIIa, 4–6 h
hematomas APTT4 PCCs, FFP
TT4
FX 1 in 1 million F10 (13q34) Umbilical stump bleeding, CNS bleeds, PT[ PCC, FFP 40–60 h
hemarthrosis, and muscle hematomas APTT[
TT4
FXI 1 in 1 million F11 (4q35.2) Postsurgical hemorrhage PT4 pdFXI, FFP 40–70 h
APTT[
TT4
FXIII 1 in 2 million F13B (1q31.3) Umbilical stump bleeding, CNS bleeds, PT4 pdFXIII, rFXIII, 11–14 d
F13A (6p25.1) hemarthrosis, and muscle hematomas APTT4 cryoprecipitate,
TT4a FFP

[ Indicates prolonged; 4 indicates normal.

Abbreviations: CNS, central nervous system; FGA, fibrinogen a-chain gene; FGB, fibrinogen b-chain gene; FGG, fibrinogen g-chain gene; PCCs, prothrombin com-
plex concentrate; pd, plasma-derived viral inactivated; rFVIII, recombinant FVIII; rFVIIa, recombinant activated factor VII; rFXIII, recombinant factor XIII.
a
Note that the global coagulation assays, APTT, PT, and TT, yield completely normal results in patients with FXIII deficiency.
 Abnormalities of Coagulation 1435

individuals being homozygous or compound heterozygous for disease-causing muta-

tions. Data collected from international registries show a variable prevalence for homo-
zygous forms, with FVII (1 in 500,000) deficiency being the most prevalent and
prothrombin and FXIII (1 in 1–2 million) deficiencies being the least prevalent.91–93 Given
the rarity of these conditions, their molecular basis, phenotypic manifestations, and ther-
apeutic modalities are less well understood as compared to hemophilia and VWD.
Bleeding risk in patients with RICD is less predictable as compared to HA and HB, and
definitions of severity used for patients with hemophilia cannot be applied to patients
with RICD.88 The scientific and standardization committee of the ISTH concluded that
while there was a strong association between clinical severity and coagulation factor
activity for fibrinogen, FII, FX, and FXIII deficiencies; there was poor to no association
for FV, FVII, and FXI deficiencies.94 Typical bleeding symptoms in patients with RICD
include epistaxis, menorrhagia, and bleeding after dental and surgical interventions.
Severe life-threatening hemorrhage, including bleeding from the umbilical cord, recur-
rent hemoperitoneum with ovulation, and hemarthrosis are reported in patients with FII,
FX, and FXIII deficiencies. Recurrent first-trimester pregnancy loss is typically seen with
afibrinogenemia, and ICH is associated with both afibrinogenemia and FXIII defi-
ciency.94 Attention must be paid to women affected by RICD, as they may experience
significant menorrhagia and postpartum hemorrhage.
Standard coagulation assays (APTT, PT, and thrombin time [TT]) may be used to
screen patients suspected of having an RICD (Table 3). Based on the results, specific
assays of factor coagulant activity can be performed to confirm the diagnosis. Standard
laboratory screening assays (APTT, PT/INR, and TT) are however, completely normal in
patients with FXIII deficiency. The ISTH recommends using a quantitative functional
FXIII assay for screening for FXIII deficiency followed by measurement of FXIII-A2B2
antigen concentration to confirm the diagnosis.95 Once a diagnosis of RICD is made,
patients should be referred to a specialty center for further evaluation and manage-
ment. Similar to hemophilia, replacement of the deficient coagulation factor forms
the mainstay of therapy for RICD.89 Plasma-derived, viral-inactivated factor concen-
trates are available for fibrinogen, FVII, FXI, and FXIII,91,92,96,97 whereas recombinant
factor concentrates are available only for FVII (NovoSeven), and more recently for FXIII
(NovoThirteen).98 There are no purified factor concentrates currently available for FII,
FV, and FX, and bleeding in these conditions can be treated with FFP or prothrombin
complex concentrates (for FII and FX deficiencies).99–101 In patients with RICD, factor
concentrates are usually used on-demand, although prophylactic replacement is
recommended for patients with FXIII deficiency97 and for select patients with severe
deficiencies of FVII and fibrinogen who have sustained life-threatening bleeds. Antifibri-
nolytic agents such as ε-aminocaproic acid and tranexamic acid may be used for
mucosal bleeds. Hormonal therapy with estrogen-containing oral contraceptive pills
may be used in patients with menorrhagia.89 Characteristic clinical findings, molecular
basis, laboratory abnormalities, and factor concentrates available for the RICD are
summarized in Table 3. For more advanced reading on the laboratory diagnosis and
clinical management of RICD, the reader is referred to recommendations made by
the United Kingdom Haemophilia Centre Doctors’ Association (UKHC-DO).102

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